CLINICAL PHARMACOLOGY

Mechanism of Action

Pharmacokinetics

Multiple dose ribavirin
pharmacokinetic data are available for HCV patients who received ribavirin in
combination with peginterferon alfa-2a. Following administration of 1200 mg/day
with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC0-12hr
was 25,361±7110 ng·hr/mL and Cmax was 2748±818 ng/mL. The average time to reach
Cmax was 2 hours. Trough ribavirin plasma concentrations following 12
weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who
received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200
mg/day (n=75; body weight greater than 75 kg).

The terminal half-life of ribavirin following
administration of a single oral dose of COPEGUS is about 120 to 170 hours. The
total apparent clearance following administration of a single oral dose of
COPEGUS is about 26 L/h. There is extensive accumulation of ribavirin after
multiple dosing (twice daily) such that the Cmax at steady state was four-fold
higher than that of a single dose.

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was
increased by co-administration with a high-fat meal. The absorption was slowed
(Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%,
respectively, when COPEGUS was taken with a high-fat meal compared with fasting
conditions [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

Elimination and Metabolism

The contribution of renal and hepatic pathways to
ribavirin elimination after administration of COPEGUS is not known. In vitro
studies indicate that ribavirin is not a substrate of CYP450 enzymes.

Renal Impairment

A clinical trial evaluated 50 CHC subjects with either
moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance
less than 30 mL/min) renal impairment or end stage renal disease (ESRD)
requiring chronic hemodialysis (HD). The apparent clearance of ribavirin was
reduced in subjects with creatinine clearance less than or equal to 50 mL/min,
including subjects with ESRD on HD, exhibiting approximately 30% of the value
found in subjects with normal renal function. Pharmacokinetic modeling and
simulation indicates that a dose of 200 mg daily in patients with severe renal
impairment and a dose of 200 mg daily alternating with 400 mg the following day
in patients with moderate renal impairment will provide plasma ribavirin
exposures similar to that observed in patients with normal renal function
receiving the standard 1000/1200 mg COPEGUS daily dose. These doses have not
been studied in patients.

In 18 subjects with ESRD receiving chronic HD, COPEGUS
was administered at a dose of 200 mg daily. Ribavirin plasma exposures in these
subjects were approximately 20% lower compared to subjects with normal renal function
receiving the standard 1000/1200 mg COPEGUS daily dose [see DOSAGE AND
ADMINISTRATION, Use In Specific Populations].

Plasma ribavirin is removed by hemodialysis with an
extraction ratio of approximately 50%; however, due to the large volume of
distribution of ribavirin, plasma exposure is not expected to change with
hemodialysis.

Microbiology

Mechanism of Action

The mechanism by which ribavirin contributes to its
antiviral efficacy in the clinic is not fully understood. Ribavirin has direct
antiviral activity in tissue culture against many RNA viruses. Ribavirin
increases the mutation frequency in the genomes of several RNA viruses and
ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV
replicon), ribavirin inhibited autonomous HCV RNA replication with a 50%
effective concentration (EC50) value of 11-21 mcM. In the same model, PEG-IFN
α-2a also inhibited HCV RNA replication, with an EC50 value of 0.1-3
ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at
inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical
variability in their response to PEG-IFN-α and ribavirin therapy. Viral
genetic determinants associated with the variable response have not been
definitively identified.

Cross-resistance

Cross-resistance between IFN α and ribavirin has not
been observed.

Animal Toxicology

In a study in rats, it was concluded that dominant
lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up
to 1.7 times the maximum recommended human dose of ribavirin).

Long-term studies in the mouse and rat (18 to 24 months;
dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4
times the maximum daily human dose of ribavirin) have demonstrated a
relationship between chronic ribavirin exposure and an increased incidence of
vascular lesions (microscopic hemorrhages) in mice. In rats, retinal
degeneration occurred in controls, but the incidence was increased in
ribavirin-treated rats.

Clinical Studies

Chronic Hepatitis C Patients

Adult Patients

The safety and effectiveness of PEGASYS in combination
with COPEGUS for the treatment of hepatitis C virus infection were assessed in
two randomized controlled clinical trials. All patients were adults, had
compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis
of chronic hepatitis, and were previously untreated with interferon.
Approximately 20% of patients in both studies had compensated cirrhosis
(Child-Pugh class A). Patients coinfected with HIV were excluded from these
studies.

In Study NV15801, patients were randomized to receive
either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS
180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight less than 75 kg)
or 1200 mg by mouth (body weight greater than or equal to 75 kg) or interferon
alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg
by mouth. All patients received 48 weeks of therapy followed by 24 weeks of
treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded.
Sustained virological response was defined as undetectable (less than 50 IU/mL)
HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted
in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table
9). In all treatment arms, patients with viral genotype 1, regardless of viral
load, had a lower response rate to PEGASYS in combination with COPEGUS compared
to patients with other viral genotypes.

In Study NV15942, all patients
received PEGASYS 180 mcg subcutaneous once weekly and were randomized to
treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or
1000 mg/1200 mg (for body weight less than 75 kg/greater than or equal to 75
kg). Assignment to the four treatment arms was stratified by viral genotype and
baseline HCV viral titer. Patients with genotype 1 and high viral titer
(defined as greater than 2 x 106 HCV RNA copies/mL serum) were
preferentially assigned to treatment for 48 weeks.

Sustained Virologic Response
(SVR) and HCV Genotype

HCV 1 and 4-Irrespective of
baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200
mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the
end of the 24-week treatment-free follow-up period) compared to shorter treatment
(24 weeks) and/or 800 mg COPEGUS.

*1000 mg for body weight less
than 75 kg; 1200 mg for body weight greater than or equal to 75 kg.

Pediatric Patients

Previously untreated pediatric
subjects 5 through 17 years of age (55% less than 12 years old) with chronic
hepatitis C, compensated liver disease and detectable HCV RNA were treated with
COPEGUS approximately 15 mg/kg/day plus PEGASYS 180 mcg/1.73 m² x
body surface area once weekly for 48 weeks. All subjects were followed for 24
weeks post-treatment. Sustained virological response (SVR) was defined as
undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of
114 subjects were randomized to receive either combination treatment of COPEGUS
plus PEGASYS or PEGASYS monotherapy; subjects failing PEGASYS monotherapy at 24
weeks or later could receive open-label COPEGUS plus PEGASYS. The initial
randomized arms were balanced for demographic factors; 55 subjects received
initial combination treatment of COPEGUS plus PEGASYS and 59 received PEGASYS
plus placebo; in the overall intent-to-treat population, 45% were female, 80%
were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are
summarized in Table 11.

In studies NV15801 and NV15942,
lack of early virologic response by 12 weeks (defined as HCV RNA undetectable
or greater than 2 log10 lower than baseline) was grounds for discontinuation of
treatment. Of patients who lacked an early viral response by 12 weeks and
completed a recommended course of therapy despite a protocol-defined option to
discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an
early viral response by 24 weeks, 19 completed a full course of therapy and
none achieved an SVR.

Chronic Hepatitis C/HIV
Coinfected Patients

In Study NR15961, patients with
CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once
weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by
mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus
COPEGUS 800 mg by mouth daily. All patients received 48 weeks of therapy and
sustained virologic response (SVR) was assessed at 24 weeks of treatment-free
follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS
treatment arms. All patients were adults, had compensated liver disease, detectable
hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were
previously untreated with interferon. Patients also had CD4+ cell count greater
than or equal to 200 cells/mm³ or CD4+ cell count greater than or
equal to 100 cells/mm³ but less than 200 cells/mm³ and
HIV-1 RNA less than 5000 copies/mL, and stable status of HIV. Approximately 15%
of patients in the study had cirrhosis. Results are shown in Table 12.

Of the patients who did not
demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from
baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination
therapy, 2% (2/85) achieved an SVR.

In CHC patients with HIV
coinfection who received 48 weeks of PEGASYS alone or in combination with
COPEGUS treatment, mean and median HIV RNA titers did not increase above
baseline during treatment or 24 weeks post treatment.

Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.